Nicotine is a major addictive drug that recruits the endogenous opioid system for some of its addictive effects. We have validated sophisticated behavioral models for the evaluation of genetic factors that contribute to nicotine addiction in mice. These models will be used in conventional and tissue-specific opioid receptor and opioid peptide knockout mice to dissect the participation of opioid mechanisms in nicotine addiction and to identify genes related to nicotine consumption downstream of the opioid system. The specific aims will be: Specific Aim 1. To evaluate the involvement of opioid receptors and endogenous opioid peptides in the different components of nicotine addiction. Specific Aim 2. To validate the behavioral changes observed in Aim 1 and clarify neural sites involved by using conditional tissue-specific knockout of opioid receptor and peptide genes. Specific Aim 3. To identify genes regulated by nicotine downstream the opioid system. The potential impact of results obtained in this research project is of importance since nicotine addiction constitutes a major problem of public health in the world. These results will help to identify potential targets for the development of novel therapeutic strategies against nicotine addiction. Therefore, this project could provide a major progress in the management of nicotine dependence, and could have repercussions to improve the quality of live in the societies widely affected by the health and social-economic problems associated with nicotine addiction. Finally, the results and experimental strategies of this project would be also of interest for the study of other addictive processes, considering that the opioid system represents a common substrate to the addictive properties of most drugs of abuse.